Preparation method and intermediate of superior tiderone

Abstract

The invention relates to the technical field of organic synthesis, particularly discloses a preparation method of superior tiderone and an intermediate of superior tiderone, and provides a gram-scale superior tiderone synthesis route which is simple, efficient, simple in reaction operation and easy to amplify. The longest linear step 12 of the route is the shortest synthetic route in the current molecular synthesis report. In addition, initial raw materials and synthetic reagents are cheap and easy to obtain, and the cost of synthetic materials is greatly reduced. According to the route, a highly-converged synthesis strategy is adopted, and fragment assembly is more flexible. Therefore, on the basis of the route, a plurality of fragments are subjected to derivatization modification and assembly, and a structure based on the optitiderone can be efficiently obtained, so that a solid material foundation is laid for finding anti-tumor active molecules.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and specifically discloses a preparation method of eutideron and an intermediate thereof. Background Art

[0002] Utidelone, independently developed by Biostar, is China's first innovative Class 1 epothilone anti-tumor drug. As a genetically engineered microtubule stabilizer and epothilone B analog, it promotes tubulin polymerization, stabilizes microtubule structure, and induces apoptosis. The launch of Utidelone provides an important new treatment option for patients with advanced breast cancer.

[0003]

[0004] Currently, there are two main methods for synthesizing Eudilon. Beijing Huahao Zhongtian and Bryan Julien et al. achieved the synthesis of Eudilon and its analogs through bio-fermentation synthesis (CN03103031.9; CN200710199560.4; Antimicrob. Agents Chemother. 2002, 46 , 2772). However, the difficulties of biosynthesis are 1) low shaker level, insufficient production capacity, and difficulty in scale-up; 2) slow growth rate; 3) low maturity of production process and equipment, and high production cost. In addition, the preparation of eutilide by chemical synthesis has been reported many times ( Nature. 1997 , 36, 757; Angew. Chem., Int. Ed. 1997 , 36, 2097; J. Am. Chem. Soc. 1997 , 119, 10073 ; J. Am. Chem. Soc. 1997 , 119, 7974; Tetrahedron Lett. 2004, 45 , 1945), the aforementioned studies reported a synthesis involving 16-25 steps. The construction of the key chiral center was achieved through either equivalent Evans group induction or substrate induction. Consequently, the synthesis process was lengthy and inefficient, resulting in high costs and incompatible with current requirements for green chemistry and precision synthesis. More importantly, due to the limitations of the synthetic methods and strategies, the aforementioned synthetic route was only capable of synthesizing milligram-scale quantities of the final product, significantly limiting the development and application of euterol. Given these bottlenecks, there is an urgent need to develop a more streamlined and efficient synthetic route capable of producing euterol on a gram-scale. Summary of the Invention

[0005] In order to solve the above technical problems, the first aspect of the present invention provides a eutidrone intermediate, as shown in Formula I, comprising:

[0006] The X is selected from CHR, -C(=O)-, and the R is selected from hydroxyl, hydrogen; Optionally, the hydrogen on the hydroxy group is replaced by a hydroxy protecting group.

[0007] In some specific embodiments of the eutideron intermediate of formula I described in the first aspect, the hydroxyl protecting group is selected from any one of TBS, TBDMS, TMS, DMT, and Trityl.

[0008] The second aspect of the present invention provides a specific form of the intermediate of Formula I described in the first aspect, comprising: or

[0009] The third aspect of the present invention provides a method for preparing Euteron, comprising compound 4, The compound 4 is dissolved in a first organic solvent, a reducing agent is added, the reaction is carried out under temperature control, an organic phase is obtained, and the organic phase is dried and concentrated to obtain a first oily substance; Under an inert gas atmosphere, PPh3CH3Br is mixed with a second organic solvent, and a base is added to obtain a reaction mixture; the first oily substance is then dissolved in a third organic solvent and added to the reaction mixture to obtain compound 5;

[0010] The base is selected from any one or a combination of LiHMDS, NaHMDS, LDA, and tBuOK; The reducing agent is selected from diisobutylaluminum hydride and lithium aluminum tetrahydride; The compound 5 undergoes one or more steps of reaction to obtain eutidrone. Optionally, the one or more steps of reaction can be referred to the synthesis method of fragments one, two, three or the examples.

[0011] In some embodiments, the molar ratio of compound 4 to DIBALH is 1:(0.8-1.3). In some embodiments, the molar ratio of compound 4 to DIBALH is optionally 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2.

[0012] In some embodiments, the molar ratio of the PPh3CH3Br to KHMDS is 1:(0.8~1.5). In some embodiments, the molar ratio of the PPh3CH3Br to KHMDS is optionally 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, or 1:1.4.

[0013] The fourth aspect of the present invention provides another method for preparing Euteron, comprising compound 3, , dissolve compound 3 in a third organic solvent, add catalyst [Ir(COD)Cl]2 / ( R )-f-phamidol, pressurized under hydrogen atmosphere to obtain compound 3-I,

[0014] Compound 3-Ⅰ is protected by hydroxyl group to obtain compound 4. ; The catalyst [Ir(COD)Cl]2 / ( R )-f-phamidol is composed of ligand ( R )-f-phamidol and [Ir(COD)Cl]2 in an organic solvent environment, followed by hydrogenation in an autoclave.

[0015] The compound 4 undergoes one or more steps of reaction to obtain Euteron. Optionally, the one or more steps of reaction can refer to the synthesis method of fragments 1, 2, 3 or the examples.

[0016] In some embodiments, the compound 3 and the catalyst [Ir(COD)Cl]2 / ( R )-f-phamidol feed molar ratio is (200~1000):1, in some embodiments, the compound 3 and the catalyst [Ir(COD)Cl]2 / ( R The molar ratio of )-f-phamidol is optionally 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1.

[0017] In some embodiments, the hydrogen is pressurized to above 60 bar, in some embodiments, the hydrogen is pressurized to above 70 bar, in some embodiments, the hydrogen is pressurized to above 80 bar, and in some embodiments, the hydrogen is pressurized to above 90 bar.

[0018] The fifth aspect of the present invention provides another method for preparing Euteron, comprising: , compound 2 is mixed with a fourth organic solvent to obtain a mixed solution; oxalyl chloride is added to the mixed solution, reacted, and the organic solvent is removed to obtain reactant A; N-methoxymethylacetamide is mixed with a fifth organic solvent, and a base is added to obtain a first reaction solution; reactant A is mixed with the fifth organic solvent, added to the first reaction solution, and reacted to obtain compound 3,

[0019] The base is selected from any one or a combination of LiHMDS, NaHMDS, LDA, and tBuOK; The compound 3 undergoes one or more steps of reaction to obtain eutidrone. Optionally, the one or more steps of reaction can refer to the synthesis method of fragments one, two, three or the examples.

[0020] In some embodiments, optionally, the molar ratio of the compound 2 to oxalyl chloride is 1:(0.5~3). In some embodiments, the molar ratio of the compound 2 to oxalyl chloride is optionally 1:0.5, 1:1, 1:1.5, 1:2.5, 1:3.

[0021] In some embodiments, optionally, the molar ratio of N-methoxymethylacetamide to base is (1-2):(1-2). In some embodiments, the molar ratio of N-methoxymethylacetamide to base is 1:1.

[0022] The sixth aspect of the present invention provides another method for preparing Euteron, comprising: compound 6, , compound 6 is mixed with a fifth organic solvent, and in the presence of a catalyst Ru(OAc)2(( R )- O -SDP) and pressurized hydrogen to obtain compound 8,

[0023] The catalyst Ru(OAc)2(( R )- O -SDP) by ligand O- SDP and [RuCl2(benzene)]2 are complexed in alkaline and organic solvent environments. The compound 8 undergoes one or more steps of reaction to obtain eutidrone. Optionally, the one or more steps of reaction can refer to the synthesis method of fragments one, two, three or the examples.

[0024] In some embodiments, the compound 6 is reacted with the catalyst Ru(OAc)2(( R )- O-SDP) is fed in a molar ratio of (100-10000): 1. In some embodiments, the compound 6 and the catalyst Ru(OAc)2(( R )- O -SDP) is optionally fed in a molar ratio of 200:1, 500:1, 1000:1, or 2000:1.

[0025] In some embodiments, the pressure of the hydrogen pressurization is greater than 20 bar. In some embodiments, the pressure of the hydrogen pressurization is greater than 30 bar, 40 bar, 50 bar, 60 bar, 70 bar, or 80 bar.

[0026] The seventh aspect of the present invention provides a method for preparing Euteron, comprising compound 8, , in an inert gas atmosphere, PPh3CH3Br is mixed with the sixth organic solvent, and then added n BuLi, to obtain a first mixture, compound 8 is added to the first mixture to react to obtain compound 9, , The compound 9 undergoes one or more steps of reaction to obtain Euteron. Optionally, the one or more steps of reaction can refer to the synthesis method of fragments one, two, three or the examples.

[0027] In some embodiments, the molar ratio of compound 8 to PPh3CH3Br is 1:(1~6). In some embodiments, the molar ratio of compound 8 to PPh3CH3Br is optionally 1:1, 1:2, 1:3, 1:4, 1:5, or 1:6.

[0028] In some embodiments, the n The molar ratio of BuLi to PPh3CH3Br is 1:(0.5~1.5). In some embodiments, n The molar ratio of BuLi to PPh3CH3Br is optionally 1:0.5, 1:1, or 1:1.5.

[0029] The eighth aspect of the present invention provides another method for preparing Euteron, comprising compound 9, The compound 9 is mixed with the seventh organic solvent, CDI, methoxymethylamine salt and base are added to react to obtain compound 10.

[0030] The methoxymethylamine salt is selected from the hydrochloride of methoxymethylamine; The compound 10 undergoes one or more steps of reaction to obtain eutidrone. Optionally, the one or more steps of reaction can be referred to the synthesis method of fragments one, two, three or the examples.

[0031] In some embodiments, the molar ratio of compound 9 to NH(OMe)Me HCl is 1:(0.8-1.2). In some embodiments, the molar ratio of compound 9 to NH(OMe)Me HCl is optionally 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2.

[0032] In some embodiments, the base is selected from one or more of Et3N, sodium carbonate, and sodium hydroxide.

[0033] In some embodiments, the molar ratio of compound 9 to CDI is 1:(0.8~1.2). In some embodiments, the molar ratio of compound 9 to CDI is optionally 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2.

[0034] The ninth aspect of the present invention provides another method for preparing Euteron, comprising compound 10, The compound 10 is dissolved in an eighth organic solvent, and DIBALH is added to obtain compound 11. , The compound 11 undergoes one or more steps of reaction to obtain eutidrone. Optionally, the one or more steps of reaction can be referred to the synthesis method of fragments one, two, three or the examples.

[0035] In some embodiments, the molar ratio of compound 10 to DIBALH is 1:(0.7~1.4). In some embodiments, the molar ratio of compound 10 to DIBALH is optionally 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, or 1:1.3.

[0036] In some embodiments, optionally, the first organic solvent, the second organic solvent, the third organic solvent, the fourth organic solvent, the fifth organic solvent, the sixth organic solvent, and the seventh organic solvent are each independently selected from one or more of dichloromethane, chloroform, ethyl acetate, toluene, ethanol, methanol, ethylene glycol, acetone, tetrahydrofuran, isopropanol, n-hexane, DMF, and acetonitrile; The drugs used in the present invention are purchased from the open legal market and have not been further purified.

[0037] In the present invention, in some embodiments, the room temperature is 0-45°C, in some embodiments, the room temperature is 5-40°C, in some embodiments, the room temperature is 10-35°C, in some embodiments, the room temperature is 15-30°C, in some embodiments, the room temperature is 20-25°C, and in some embodiments, the room temperature is 25°C.

[0038] Specifically, the present invention provides a method for synthesizing eutidrone, wherein the steps of the method include fragment 1, fragment 2, and total synthesis of eutidrone: Specifically, the synthesis of fragment 1 includes:

[0039] Specifically, the synthesis of fragment 2 includes:

[0040] Total synthesis of Eudyldron (fragment 3), including:

[0041] The drugs used in the present invention are purchased from the open legal market and have not been further purified.

[0042] Advantages of the invention: The present invention provides a concise and efficient, gram-scale synthesis route for Utidron, which is simple to operate and easily scalable. The longest linear step in this route is 12, making it the shortest synthesis route reported for the synthesis of this molecule. In addition, the starting materials and synthetic reagents are inexpensive and readily available, greatly reducing the cost of synthetic materials. This route adopts a highly convergent synthesis strategy, which is more flexible for the assembly of fragments. Therefore, based on this route, multiple fragments can be derivatized and assembled to efficiently obtain derivatives based on the structure of Utidron, thereby laying a solid material foundation for the discovery of anti-tumor active molecules. DETAILED DESCRIPTION

[0043] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0044] Example 1:

[0045] Compound 2 (19.5 mmol, 1 equiv.) was dissolved in anhydrous dichloromethane (50 mL). Two drops of DMF were then added dropwise to the reaction flask under an argon atmosphere at room temperature. Oxalyl chloride (39 mmol, 2 equiv.) was then slowly added dropwise to the reaction solution. The color of the reaction solution gradually changed from colorless and transparent to yellow. The reaction was stirred at room temperature for 2 hours and then dried under reduced pressure in an argon atmosphere.

[0046] In another reaction flask, N-methoxymethylacetamide (58.5 mmol, 3 equiv.) was added to anhydrous tetrahydrofuran (40 mL), and LDA (29.3 mL, 3 equiv.) was slowly added thereto at -78°C. The temperature was maintained and the reaction was carried out for 0.5 h to obtain a reaction solution.

[0047] The acyl chloride prepared by vacuum spin drying was then dissolved in anhydrous tetrahydrofuran (10 mL) and added to the reaction solution. After addition, the reaction was monitored by TLC and quenched with saturated ammonium chloride. The mixture was separated, extracted, concentrated, and dried. The residue was purified by column chromatography (PE:EA = 5:1) to afford 3 as a yellow oil (yield 62%).

[0048] 1 H NMR (400 MHz, CDCl3) δ 13.92 (s, 0.26H), 7.46 (s, 0.75H), 7.35 (s,1H), 7.14 (s, 0.3H), 5.76 (s, 0.29H), 3.94 (s, 1.67H), 3.70 (s, 0.67H), 3.62(s, 2.36H), 3.22 – 3.13 (m, 3H), 2.71 – 2.64 (m, 3H), 2.30 (s, 0.77H), 2.22(s, 2.37H). (Compound 3 undergoes enolic interconversion. The enolic product is present in the spectrum. There is a ratio, therefore, there are non-integer hydrogens.) 13 C NMR(101 MHz, CDCl3) δ 195.3, 172.6, 168.9, 165.4, 165.0, 152.7,151.5, 136.8, 132.2, 131.0, 124.4, 122.1, 120.0, 85.3, 61.3, 61.2, 60.2,43.4, 32.1, 31.9, 29.5, 26.8, 19.3, 19.1, 13.8, 13.2. Example 2:

[0049] Catalyst [Ir(COD)Cl]2 / ( R Preparation of )-f-phamidol: In a glove box, [Ir(COD)Cl]2 (0.048 mmol), ( R)-f-phamidol (0.1 mmol) was added to anhydrous isopropanol (2 mL) to obtain a reaction solution. The reaction solution was reacted at room temperature under argon for 3 hours. The reaction bottle was then placed in an autoclave, sealed, and removed from the glove box. The autoclave was replaced with hydrogen three times, then pressurized to 40 bar and allowed to react at room temperature overnight. After the reaction was completed, the solution was concentrated under argon to obtain a brown-yellow powder product [Ir(COD)Cl]2 / ( R )-f-phamidol.

[0050] Compound 3 (20 mmol, 1 equiv.) was dissolved in anhydrous toluene, and the previously prepared [Ir(COD)Cl]2 / ( R )-f-phamidol (0.1 mmol, 0.005 equiv.) catalyst was added to the reaction flask under argon. The flask was then transferred to an autoclave and pressurized to 60 bar with hydrogen. After the reaction was allowed to proceed at room temperature for 24 hours, the pressure was slowly released, and the reaction mixture was concentrated and purified by column chromatography (PE:EA = 2:1) to afford 3-I as a yellow oil (96% yield). 1 H NMR(600 MHz, CDCl3) δ 6.94 (s, 1H), 6.62 (s, 1H), 4.62 – 4.56 (m,1H), 4.05 (s, 1H), 3.67 (s, 3H), 3.20 (s, 3H), 2.81 – 2.74 (m, 1H), 2.71 –2.62 (m, 4H), 2.07 (s, 3H). 13 C NMR(151 MHz, CDCl3) δ 173.4, 164.5, 152.8, 140.4, 118.8, 115.8,73.0, 61.3, 37.2, 31.9, 19.1, 14.9. Example 3:

[0051] Compound 3-I (5.6 mmol, 1 equiv.) was dissolved in anhydrous dichloromethane (40 mL). 2,6-lutidine (30.8 mmol, 5.5 equiv.) and TBSOTf (27.8 mmol, 5 equiv.) were added sequentially to the reaction mixture at -78°C. After stirring at -78°C for 10 minutes, the reaction mixture was brought to room temperature overnight. After completion of the reaction, the reaction was monitored by TLC and quenched with saturated sodium bicarbonate solution. The liquid was separated, extracted, concentrated, and dried. The residue was purified by column chromatography (PE:EA = 10:1) to afford 4 as a yellow oil (95% yield).

[0052] 1 H NMR (400 MHz, CDCl3) δ 6.91 (s, 1H), 6.56 (s, 1H), 4.73 (dd, J = 9.3,3.6 Hz, 1H), 3.70 (s, 3H), 3.17 (s, 3H), 2.94 (dd, J = 14.3, 9.4 Hz, 1H), 2.69(s, 3H), 2.37 (dd, J = 14.3, 3.7 Hz, 1H), 2.05 (s, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ 171.8, 164.5, 153.1, 141.7, 118.9, 115.4,75.3, 61.3, 39.5, 32.0, 25.8, 19.2, 18.1, 14.1, -4.8, -5.2. Example 4:

[0053] Compound 4 (6.32 mmol, 1 equiv.) was dissolved in tetrahydrofuran (50 mL), and DIBALH (6.95 mmol, 1.1 equiv.) was slowly added dropwise at -78°C and allowed to react for 2 h. After the reaction was completed by TLC monitoring, potassium sodium tartrate was added to quench the reaction. The mixture was stirred at room temperature until the flocs disappeared to obtain a clear solution. The solution was diluted with ethyl acetate, the liquids were separated, and the combined organic phases were dried and concentrated to obtain a light yellow oil, which was used directly in the next step without further purification.

[0054] PPh3CH3Br (19 mmol, 3 equiv.) was dissolved in anhydrous tetrahydrofuran (20 mL) and placed at 0°C under an argon atmosphere. KHMDS (12.7 mL, 1.5 M, 19 mmol, 3 equiv.) was slowly added dropwise. After the addition was complete, the yellow suspension was stirred at 0°C for 1 hour. The above oil (6.32 mmol, 1 equiv.) was then dissolved in THF (10 mL) and slowly added dropwise to the reaction. After the addition was complete, the reaction was brought to room temperature and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried and concentrated to afford 5 as a yellow oil (80% yield).

[0055] Example 5:

[0056] 6-I (1 mmol, 1 equiv.) was dissolved in toluene, followed by the addition of ethylene glycol (3 mmol, 3 equiv.) and pyridinium p-toluenesulfonate hydrochloride (0.1 mmol, 0.1 equiv.). The reaction mixture was refluxed in toluene overnight. After completion of the reaction, the mixture was monitored by TLC and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 6:1) afforded 6 as a colorless oil (yield 88%). 1 H NMR (600 MHz, CDCl3) δ 6.93 – 6.89 (m, 1H), 4.00 – 3.90 (m, 4H), 2.30 (q, J = 7.7 Hz, 2H), 1.84 (s, 3H), 1.82 – 1.75 (m, 2H), 1.33 (s, 3H). 13 CNMR (151 MHz, CDCl3) δ 173.3, 144.7, 127.1, 109.5, 64.7, 37.5, 23.9, 23.6, 11.9. (The hydrogen on the carboxyl group is active hydrogen and no peak is observed) Example 6: Catalyst Ru(OAc)2(( R )- O Preparation of -SDP) The ligand O-SDP (0.1 mmol) and [RuCl2(benzene)]2 (0.1 mmol) were added to 1.5 mL of DMF. The reaction solution was stirred at 110 °C for 12 hours and then cooled to room temperature. A solution of NaOAc (200 mg) in MeOH (3 mL) was then added to the reaction solution. After the reaction solution was stirred at room temperature for 30 minutes, 4 mL of degassed water was added to precipitate a bright yellow solid, which was filtered and dried to obtain the catalyst Ru(OAc)2(( R )- O -SDP) (yield 79%).

[0057]

[0058] Compound 6 (3 mmol, 1 equiv.) was dissolved in methanol and the previously prepared Ru(OAc)2(( R )- O -SDP) (0.03 mmol, 0.01 equiv., S / C = 100) catalyst was added to the reaction flask under argon. The flask was then transferred to an autoclave and pressurized to 70 bar with hydrogen replacement. The reaction solution was stirred at room temperature for 20 hours, then the pressure was slowly released and the solution was concentrated. The residue was dissolved in dichloromethane and p-toluenesulfonic acid (3.5 mmol, 1.2 equiv.) was added. The product was purified by column chromatography (PE:EA = 8:1) to afford 8 as a pale yellow oil (90% yield).

[0059] Example 7:

[0060] PPh3CH3Br (7.68 mmol, 3 equiv.) was dissolved in anhydrous tetrahydrofuran (13 mL) and placed at 0°C under an argon atmosphere. n BuLi (4.8 mL, 1.6 M, 7.68 mmol, 3 equiv.) was added. After the addition was complete, the yellow suspension was stirred at 0°C for 1 hour. Compound 8 (2.56 mmol, 1 equiv.) was then dissolved in THF (2 mL) and slowly added dropwise to the reaction. After the addition was complete, the reaction was brought to room temperature and stirred for 22 hours. The reaction was quenched with 1N HCl, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried, and concentrated (water bath temperature 30°C, vacuum >100 mbar). The oil was purified by column chromatography (PE:EA = 10:1) to afford 9 as a pale yellow oil (92% yield).

[0061] Example 8:

[0062] Compound 9 (2.56 mmol, 1 equiv.) was dissolved in dichloromethane (20 mL). CDI (2.82 mmol, 1.1 equiv.), NH(OMe)MeHCl (2.82 mmol, 1.1 equiv.), and Et3N (2.82 mmol, 1.1 equiv.) were added sequentially at 0°C. The reaction mixture was brought to room temperature and stirred for 10 hours. After TLC confirmation, the reaction was purified by column chromatography (PE:EA = 3:1) to afford 10 as a colorless oil (90% yield).

[0063] Example 9:

[0064] Compound 10 (2.3 mmol, 1 equiv.) was dissolved in anhydrous n-hexane (10 mL), and DIBALH (1.1 ml, 2.76 mmol, 2.5 M, 1.2 equiv.) was slowly added dropwise at -78°C. After 3 hours, the reaction was complete as monitored by TLC. A saturated solution of potassium sodium tartrate was slowly added dropwise to quench the reaction. The mixture was stirred at room temperature for 15 minutes and diluted with n-hexane. The mixture was separated and extracted, dried, concentrated (water bath temperature 30°C, vacuum degree <120 mbar), and purified on a silica gel column (PE:EA 80:1) to obtain compound 11 with a melon aroma (yield 90%).

[0065] Example 10:

[0066] Compound 16 (24.64 mmol, 1 equiv.) was added to THF (70 mL) at -78°C. LDA (12.94 mL, 2 M in THF, 25.87 mmol, 1.05 equiv.) was then slowly added dropwise and maintained at this temperature for 1 hour. Compound 11 (24.64 mmol, 1 equiv.) was then slowly added to the reaction mixture. The reaction was also stirred at -78°C for 1.5 hours. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, followed by separation, extraction, concentration, and drying. The residue was purified by column chromatography (PE:EA = 50:1) to afford 17 as a pale yellow oil (70% yield).

[0067] Example 10:

[0068] Compound 17 (1.84 mmol, 1 equiv.) was dissolved in DCM (6 mL) at 0°C, and 2,6-lutidine (1.07 mL, 9.24 mmol, 5 equiv.) and TBSOTf (1.06 mL, 4.6 mmol, 2.5 equiv.) were added sequentially. The reaction mixture was allowed to react at this temperature for 3 hours, then quenched with 1N glacial hydrochloric acid, extracted with DCM, dried, and concentrated. The oil was dissolved in DCM / MeOH (V:V = 1:1, 6 mL), and camphorsulfonic acid (0.92 mmol, 0.5 equiv.) was added and reacted at 0°C for 1 hour. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried, concentrated, and purified by column chromatography (PE:EA = 30:1) to afford compound 18 (84% yield).

[0069] Example 11:

[0070] Compound 18 (2.37 mmol, 1 equiv.) was dissolved in DMF (24 mL). Silica gel (1.28 g, 80-100 mesh) and pyridinium dichromate (21.3 mmol, 9 equiv.) were added sequentially at room temperature. The reaction mixture was allowed to react at this temperature for 12 hours. TLC monitored the completion of the reaction. The mixture was filtered, extracted with tert-butyl methyl ether, dried, concentrated, and purified by column chromatography (PE:EA = 15:1) to afford 19 as a colorless oil (80% yield).

[0071] Example 12:

[0072] Compound 19 (3.66 mmol, 1 equiv.) was dissolved in DCM (20 mL). EDCI (14.64 mmol, 4 equiv.), DMAP (7.32 mmol, 2 equiv.), and compound 5 (4.03 mmol, 1.1 equiv.) were added sequentially at room temperature and stirred for 24 h. After completion of the reaction, the mixture was monitored by TLC. The mixture was diluted with dichloromethane and extracted with water. After drying and concentration, the product was purified by column chromatography (PE: EA = 10:1) to obtain a light yellow oil 20 (yield 90%).

[0073] Example 13:

[0074] In a glove box, compound 20 (7.76 mmol, 1 equiv.) was dissolved in anhydrous benzene, and Schrock catalyst (1.94 mmol, 0.25 equiv.) was added to the reaction flask. The reaction was then allowed to proceed at 55°C for 24 hours. The reaction solution was then concentrated to yield a yellow oil. This oil was dissolved in THF (5 mL), and pyridine hydrofluoride solution (2.5 mL) was slowly added dropwise under an ice bath. The reaction solution was then brought to room temperature and allowed to react for 2 hours. After completion of the reaction, the pH was adjusted to 8–9 by adding saturated sodium bicarbonate solution, and the mixture was diluted with ethyl acetate. The mixture was separated, extracted, concentrated, and dried. The residue was purified by column chromatography (PE:EA = 1:2) to afford the final product, Eutederlon (yield 41%).

[0075] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A eutilide intermediate, such as formula I, comprising: ； The X is selected from CHR or -C(=O)-, and the R is selected from hydroxyl or hydrogen; Optionally, the hydrogen on the hydroxy group is replaced by a hydroxy protecting group.

2. The Eutidenol intermediate according to claim 1, characterized in that The hydroxyl protecting group is selected from any one of TBS, TBDMS, TMS, DMT and Trityl.

3. A eutilide intermediate, specifically: 。 4. A method for preparing Utidolon, characterized in that: Including compound 4, , the compound 4 is dissolved in a first organic solvent, a reducing agent is added, the temperature is controlled to react, an organic phase is obtained, and an oily substance is obtained; Under an inert gas atmosphere, PPh3CH3Br is mixed with a second organic solvent, and a base is added to obtain a reaction mixture; the oil is then added to the reaction mixture to obtain compound 5; ； The compound 5 undergoes one or more steps of reaction to obtain Euteron.

5. A method for preparing Utidolon, characterized in that: Including compound 3, , dissolve compound 3 in a third organic solvent, add catalyst [Ir(COD)Cl]2 / ( R )-f-phamidol, pressurized under hydrogen atmosphere to obtain compound 3-I, ； Compound 3-Ⅰ is protected by hydroxyl group to obtain compound 4. ; The catalyst [Ir(COD)Cl]2 / ( R )-f-phamidol is composed of ligand ( R )-f-phamidol and [Ir(COD)Cl]2 are mixed in an organic solvent environment and hydrogenated to obtain; The compound 4 undergoes one or more steps of reaction to obtain Euteron.

6. A method for preparing Euteron, characterized in that: Including compound 2 , mixing compound 2 with a fourth organic solvent to obtain a mixed solution, adding oxalyl chloride to the mixed solution, reacting to obtain reactant A; After mixing N-methoxymethylacetamide and the fifth organic solvent, a base is added to obtain a first reaction solution; reactant A is added to the first reaction solution, and the mixture is reacted to obtain compound 3. ； The compound 3 undergoes one or more steps of reaction to obtain Euteron.

7. A method for preparing Utidolon, characterized in that: Including compound 6, , compound 6 is mixed with a fifth organic solvent, and in the presence of a catalyst Ru(OAc)2( R - O -SDP) and pressurized hydrogen to obtain compound 8, ； The catalyst Ru(OAc)2(( R )- O -SDP) by the ligand ( R )- O- SDP and [RuCl2(benzene)]2 are complexed in alkaline and organic solvent environments. The compound 8 undergoes one or more steps of reaction to obtain Euteron.

8. A method for preparing Utidolon, characterized in that: Including, compound 8, , in an inert gas atmosphere, PPh3CH3Br is mixed with the sixth organic solvent, and then added n BuLi, to obtain a first mixture, compound 8 is added to the first mixture to react to obtain compound 9, ， The compound 9 undergoes one or more steps of reaction to obtain Euteron.

9. A method for preparing Utidolon, characterized in that: Including compound 9, The compound 9 is mixed with the seventh organic solvent, CDI, methoxymethylamine salt and base are added to react to obtain compound 10. ； The compound 10 undergoes one or more steps of reaction to obtain Euteron.

10. A method for preparing Euteron, characterized in that: Including compound 10, The compound 10 is dissolved in an eighth organic solvent, and DIBALH is added to obtain compound 11. ， The compound 11 undergoes one or more steps of reaction to obtain Euteron.

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